Abstract
Migration and invasion enhancer 1 (MIEN1) is a novel gene involved in prostate cancer progression by enhancing prostate cancer cell migration and invasion. DNA methylation, an important epigenetic regulation, is one of the most widely altered mechanisms in prostate cancer. This phenomenon frames the basis to study the DNA methylation patterns in the promoter region of MIEN1. Bisulfite pyrosequencing demonstrates the MIEN1 promoter contains a short interspersed nuclear Alu element (SINE Alu) repeat sequence. Validation of methylation inhibition on MIEN1 was performed using nucleoside analogs and non-nucleoside inhibitors and resulted in an increase in both MIEN1 RNA and protein in normal cells. MIEN1 mRNA and protein increases upon inhibition of individual DNA methyltransferases using RNA interference technologies. Furthermore, dual luciferase reporter assays, in silico analysis, and chromatin immunoprecipitation assays identified a sequence upstream of the transcription start site that has a site for binding of the USF transcription factors. These results suggest the MIEN1 promoter has a SINE Alu region that is hypermethylated in normal cells leading to repression of the gene. In cancer, the hypomethylation of a part of this repeat, in addition to the binding of USF, results in MIEN1 expression.
Highlights
Epigenetic regulation of genes involves non-genetic modifications of DNA and/or histones
Our study shows that the Migration and invasion enhancer 1 (MIEN1) promoter has a short interspersed nuclear element (SINE) Short interspersed nuclear Alu element (Alu) region that is hypomethylated in cancer, resulting in an increased expression of MIEN1 in cancer [5, 28]
We determined the region to be interrogated for methylation within the MIEN1 gene that would possibly regulate the expression of MIEN1 by analyzing a previous study of high throughput methylation performed on normal and malignant ovarian epithelial and fallopian tube epithelial tissues (GSE81228) where we found the Alu region to be differentially expressed between normal and malignant tumors [29]
Summary
Epigenetic regulation of genes involves non-genetic modifications of DNA and/or histones. With the developments in the field of genomics, including generation sequencing, many genes that are altered in various cancers have been identified. Among these genes, a vast majority that are down regulated in cancers correlate to genes exhibiting hypermethylated promoters, corroborating the previous observations. A vast majority that are down regulated in cancers correlate to genes exhibiting hypermethylated promoters, corroborating the previous observations These studies, along with some others in the past, allude to the potential use of the methylation pattern signatures as biomarkers for early detection of cancer [8,9,10,11,12]
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